Synthetic programs are continuing to develop new ligands for imaging brain drug receptors by positron emission tomography (PET) and single photon emission computed tomography (SPECT) scanning, and the NIH Opiate Total Synthesis is employed to provide previously inaccessible unnatural enantiomers of opiates and derivatives. The binding characteristics, pharmacology, immunochemistry, and the multiplicity of opioid receptors were examined, and new drugs were explored as treatment agents for cocaine abuse and for their interaction with the dopamine transporter. Study of delta opioid receptors - The enantiomers, their benzylic epimeres and the corresponding methyl ethers, of the delta opioid receptor selective racemic agonist BW373U86, were synthesized from the enantiomers of 1-allyl-trans-2,5-dimethylpiperazine. Studies with these compounds in the isolated mouse vas deferensand guinea pig ileum bioassays revealed that the delta/mu selectivity of the (+)-methyl ether of BW373U86 was about 2000 fold. This compound will be a valuable tool for further study of the delta opioid receptor structure and function, including its role in addictive diseases. Potential agents for treatment and prevention of cocaine abuse - The cocaine receptor on the dopamine transporter is a logical target binding site for the design and synthesis of novel agents for evaluation as possible cocaine antagonists. Synthetic studies for the identification of drugs which will be useful in the treatment and prevention of cocaine abuse are continuing. X-ray crystal structures of potent opioid receptor ligands-As a prelude to molecular modeling and other studies of the newly cloned and expressed mu, delta, and kappa opioid receptor subtypes, X-ray crystal structures were determined for etonitazene, cis-(+)-3-methylfentanyl, and etorphine, three extremely potent opioid agonists. X-ray crystal structures were also determined for diprenorphine, a potent opioid antagonist, and buprenorphine, a clinically useful mixed agonist-antagonist.